Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays

doi:10.1016/j.bmcl.2017.03.012

	Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays
	Sun, Zhongya 1; Zhang, Hao 2,3; Chen, Zhifeng4 ; Xie, Yiqian 2; Jiang, Hao 2; Chen, Limin 1; Ding, Hong 2; Zhang, Yuanyuan 2; Jiang, Hualiang 2; Zheng, Mingyue 2; Luo, Cheng 2,3
	2017-05
发表期刊	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (IF:2.5[JCR-2023],2.4[5-Year])
ISSN	0960-894X
卷号	27 期号:9 页码:2003-2009
发表状态	已发表
DOI	10.1016/j.bmcl.2017.03.012
摘要	As an epigenetic reader, BRD4 regulates the transcription of important downstream genes that are essential for the survival of tumor cells. Small molecular inhibitors targeting the first bromodomain of BRD4 (BRD4-BD1) have showed promising potentials in the therapies of BRD4-related cancers. Through AlphaScreen-based high-throughput screening assay, a novel small molecular inhibitor was identified, and named DCBD-005, which inhibited the binding between BRD4-BD1 and acetylated lysines with an IC50 value of 0.81 +/- 0.03 mu M. The compound DCBD-005 effectively inhibited the viability, caused cell cycle arrest, and induced apoptosis in human leukemia MV4-11 cells. Moreover, the crystal structure of compound DCBD-005 with the BRD4-BD1 was determined at 1.72 angstrom resolution, which revealed the binding mechanism of the leading compound, and also provided solid basis for further structure-based optimization. These results indicated that this novel BRD4-BD1 inhibitor DCBD-005 is promising to be developed into a drug candidate in the treatment of BRD4-related diseases. (C) 2017 Published by Elsevier Ltd.
关键词	BRD4 inhibitor High-throughput screening Crystallography
收录类别	SCI
语种	英语
资助项目	Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505]
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
WOS类目	Chemistry, Medicinal ; Chemistry, Organic
WOS记录号	WOS:000399862800025
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS关键词	BET BROMODOMAIN INHIBITION ; GENE-EXPRESSION ; CHROMATIN ; TARGET ; CANCER ; POTENT ; OPTIMIZATION ; ACETYLATION ; RECOGNITION ; ACTIVATION
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1398
专题	生命科学与技术学院生命科学与技术学院_硕士生
通讯作者	Chen, Limin; Ding, Hong; Luo, Cheng
作者单位	1.Nanchang Univ, Sch Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Sun, Zhongya,Zhang, Hao,Chen, Zhifeng,et al. Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2017,27(9):2003-2009.
APA	Sun, Zhongya.,Zhang, Hao.,Chen, Zhifeng.,Xie, Yiqian.,Jiang, Hao.,...&Luo, Cheng.(2017).Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,27(9),2003-2009.
MLA	Sun, Zhongya,et al."Discovery of novel BRD4 inhibitors by high-throughput screening, crystallography, and cell-based assays".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 27.9(2017):2003-2009.